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Ali Yousefian-JaziAli Yousefian-Jazi
한국과학기술연구원
Mol. Neurodegener., Feb 07 2025, 20 (1) 16 | https://doi.org/10.1186/s13024-024-00792-y
Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice
Ali Yousefian-Jazi1, Suhyun Kim1, Jiyeon Chu1,2, Seung-Hye Choi11, Phuong Thi Thanh Nguyen1,3, Uiyeol Park1,4, Min-gyeong Kim3,5, Hongik Hwang6, Kyungeun Lee7, Yeyun Kim1,2, Seung Jae Hyeon1, Hyewhon Rhim5, Hannah L. Ryu8, Grewo Lim8,9, Thor D. Stein8,9, Kayeong Lim5, Hoon Ryu1,3,10* and Junghee Lee8,9*
1Laboratory for Brain Gene Regulation and Epigenetics, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
2Department of Integrated Biomedical and Life Science, College of Health Science, Korea University, Seoul 02841, Republic of Korea
3KIST School, Division of Bio-Medical Science & Technology, University of Science and Technology (UST), Seoul 02792, Republic of Korea
4Department of Biochemistry & Molecular Biology, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea
5Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
6Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea
7Advanced Analysis Data Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
8Boston University Alzheimer’s Disease Research Center and Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA
9VA Boston Healthcare System, Boston, MA 02130, USA
10KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea
11Severance Biomedical Science Institute, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
Corresponding authors
Correspondence to Hoon Ryu or Junghee Lee.
1Laboratory for Brain Gene Regulation and Epigenetics, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
2Department of Integrated Biomedical and Life Science, College of Health Science, Korea University, Seoul 02841, Republic of Korea
3KIST School, Division of Bio-Medical Science & Technology, University of Science and Technology (UST), Seoul 02792, Republic of Korea
4Department of Biochemistry & Molecular Biology, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea
5Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
6Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea
7Advanced Analysis Data Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
8Boston University Alzheimer’s Disease Research Center and Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA
9VA Boston Healthcare System, Boston, MA 02130, USA
10KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea
11Severance Biomedical Science Institute, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
Corresponding authors
Correspondence to Hoon Ryu or Junghee Lee.
Abstract
Background
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, leading to progressive paralysis. Both genetic alterations and epigenetic modifications contribute to neuronal dysfunction in the pathogenesis of ALS. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear.
Methods
Convolutional neural network was used to identify an ALS-associated SNP located in the intronic region of MEF2C (rs304152), residing in a putative enhancer element. To examine the alteration of MEF2C transcription by the SNP, we generated HEK293T cells carrying the major or minor allele by CRISPR-Cas9. To verify the role of MEF2C-knockdown (MEF2C-KD) in mice, we developed AAV expressing shRNA for MEF2C based on AAV-U6 promoter vector. Neuropathological alterations of MEF2C-KD mice with mitochondrial dysfunction and motor neuronal damage were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through longitudinal study by tail suspension, inverted grid test and automated gait analysis.
Results
Here, we show that enhancer mutation of MEF2C reduces own gene expression and consequently impairs mitochondrial function in motor neurons. MEF2C localizes and binds to the mitochondria DNA, and directly modulates mitochondria-encoded gene expression. CRISPR/Cas-9-induced mutation of the MEF2C enhancer decreases expression of mitochondria-encoded genes. Moreover, MEF2C mutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress. MEF2C deficiency in the upper and lower motor neurons of mice impairs mitochondria-encoded genes, and leads to mitochondrial metabolic disruption and progressive motor behavioral deficits.
Conclusions
Together, MEF2C dysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, leading to progressive paralysis. Both genetic alterations and epigenetic modifications contribute to neuronal dysfunction in the pathogenesis of ALS. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear.
Methods
Convolutional neural network was used to identify an ALS-associated SNP located in the intronic region of MEF2C (rs304152), residing in a putative enhancer element. To examine the alteration of MEF2C transcription by the SNP, we generated HEK293T cells carrying the major or minor allele by CRISPR-Cas9. To verify the role of MEF2C-knockdown (MEF2C-KD) in mice, we developed AAV expressing shRNA for MEF2C based on AAV-U6 promoter vector. Neuropathological alterations of MEF2C-KD mice with mitochondrial dysfunction and motor neuronal damage were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through longitudinal study by tail suspension, inverted grid test and automated gait analysis.
Results
Here, we show that enhancer mutation of MEF2C reduces own gene expression and consequently impairs mitochondrial function in motor neurons. MEF2C localizes and binds to the mitochondria DNA, and directly modulates mitochondria-encoded gene expression. CRISPR/Cas-9-induced mutation of the MEF2C enhancer decreases expression of mitochondria-encoded genes. Moreover, MEF2C mutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress. MEF2C deficiency in the upper and lower motor neurons of mice impairs mitochondria-encoded genes, and leads to mitochondrial metabolic disruption and progressive motor behavioral deficits.
Conclusions
Together, MEF2C dysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-10)
- 국내(교신)+국외 연구진
- 의약학 > 신경의학
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